PMID- 18056456
OWN - NLM
STAT- MEDLINE
DCOM- 20080122
LR  - 20220310
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 23
DP  - 2007 Dec 1
TI  - Targeting protein translation in human non small cell lung cancer via combined 
      MEK and mammalian target of rapamycin suppression.
PG  - 11300-8
AB  - Lung cancer is a genetically heterogeneous disease characterized by the 
      acquisition of somatic mutations in numerous protein kinases, including 
      components of the rat sarcoma viral oncogene homolog (RAS) and AKT signaling 
      cascades. These pathways intersect at various points, rendering this network 
      highly redundant and suggesting that combined mitogen-activated 
      protein/extracellular signal-regulated kinase (MEK) and mammalian target of 
      rapamycin (mTOR) inhibition may be a promising drug combination that can overcome 
      its intrinsic plasticity. The MEK inhibitors, CI-1040 or PD0325901, in 
      combination with the mTOR inhibitor, rapamycin, or its analogue AP23573, 
      exhibited dose-dependent synergism in human lung cancer cell lines that was 
      associated with suppression of proliferation rather than enhancement of cell 
      death. Concurrent suppression of MEK and mTOR inhibited ribosomal biogenesis by 
      40% within 24 h and was associated with a decreased polysome/monosome ratio that 
      is indicative of reduced protein translation efficiency. Furthermore, the 
      combination of PD0325901 and rapamycin was significantly superior to either drug 
      alone or PD0325901 at the maximum tolerated dose in nude mice bearing human lung 
      tumor xenografts or heterotransplants. Except for a PTEN mutant, all tumor models 
      had sustained tumor regressions and minimal toxicity. These data (a) provide 
      evidence that both pathways converge on factors that regulate translation 
      initiation and (b) support therapeutic strategies in lung cancer that 
      simultaneously suppress the RAS and AKT signaling network.
FAU - Legrier, Marie-Emmanuelle
AU  - Legrier ME
AD  - Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, 
      New York 10461, USA.
FAU - Yang, Chia-Ping Huang
AU  - Yang CP
FAU - Yan, Han-Guang
AU  - Yan HG
FAU - Lopez-Barcons, Lluis
AU  - Lopez-Barcons L
FAU - Keller, Steven M
AU  - Keller SM
FAU - Perez-Soler, Roman
AU  - Perez-Soler R
FAU - Horwitz, Susan Band
AU  - Horwitz SB
FAU - McDaid, Hayley M
AU  - McDaid HM
LA  - eng
GR  - CA077263/CA/NCI NIH HHS/United States
GR  - CA083185/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Benzamides)
RN  - 0 (Immunosuppressive Agents)
RN  - 86K0J5AK6M (mirdametinib)
RN  - 9N3CBB0BIQ (Diphenylamine)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Benzamides/pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology
MH  - Cell Death/drug effects
MH  - Cell Proliferation/drug effects
MH  - Diphenylamine/analogs & derivatives/pharmacology
MH  - Drug Synergism
MH  - Drug Therapy, Combination
MH  - Feedback, Physiological
MH  - Humans
MH  - Immunoblotting
MH  - Immunosuppressive Agents/pharmacology
MH  - Lung Neoplasms/*drug therapy/metabolism/pathology
MH  - Mice
MH  - Mice, Nude
MH  - Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors/metabolism
MH  - PTEN Phosphohydrolase
MH  - Peptide Chain Initiation, Translational/*drug effects
MH  - Protein Kinases/*chemistry/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
EDAT- 2007/12/07 09:00
MHDA- 2008/01/23 09:00
CRDT- 2007/12/07 09:00
PHST- 2007/12/07 09:00 [pubmed]
PHST- 2008/01/23 09:00 [medline]
PHST- 2007/12/07 09:00 [entrez]
AID - 67/23/11300 [pii]
AID - 10.1158/0008-5472.CAN-07-0702 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Dec 1;67(23):11300-8. doi: 10.1158/0008-5472.CAN-07-0702.